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. 2015 May 10;31(6):755–762. doi: 10.1007/s12264-015-1532-2

Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage

Yu-Jing Li 1, Guo-Qiang Chang 1, Yuanchu Liu 1,2, Ye Gong 1,2, Chunsheng Yang 1, Kristofer Wood 3, Fu-Dong Shi 1,3, Ying Fu 1,✉, Yaping Yan 1,✉
PMCID: PMC5563722  PMID: 25958190

Abstract

Intracerebral hemorrhage (ICH) leads to high rates of death and disability. The pronounced inflammatory reactions that rapidly follow ICH contribute to disease progression. Our recent clinical trial demonstrated that oral administration of an immune modulator fingolimod restrained secondary injury derived from initial hematoma, but the mechanisms remain unknown. In this study, we aim to investigate the effects of fingolimod on inflammatory mediators and vascular permeability in the clinical trial of oral fingolimod for intracerebral hemorrhage (ICH). The results showed that fingolimod decreased the numbers of circulating CD4+ T, CD8+ T, CD19+ B, NK, and NKT cells and they recovered quickly after the drug was stopped. The plasma ICAM level was decreased and IL-10 was increased by fingolimod. Interestingly, fingolimod protected vascular permeability as indicated by a decreased plasma level of MMP9 and the reduced rT1%. In conclusion, modulation of systemic inflammation by fingolimod demonstrates that it is an effective therapeutic agent for ICH. Fingolimod may prevent perihematomal edema enlargement by protecting vascular permeability.

Keywords: fingolimod, inflammatory mediator, vascular permeability, intracerebral hemorrhage

Contributor Information

Ying Fu, Email: yfu@tijmu.edu.cn.

Yaping Yan, Email: yaping.yan@tijmu.edu.cn.

References

  • [1].Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373:1632–1644. doi: 10.1016/S0140-6736(09)60371-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Ribo M, Grotta JC. Latest advances in intracerebral hemorrhage. Curr Neurol Neurosci Rep. 2006;6:17–22. doi: 10.1007/s11910-996-0004-0. [DOI] [PubMed] [Google Scholar]
  • [3].van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–176. doi: 10.1016/S1474-4422(09)70340-0. [DOI] [PubMed] [Google Scholar]
  • [4].Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–1460. doi: 10.1056/NEJM200105103441907. [DOI] [PubMed] [Google Scholar]
  • [5].Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol. 2010;92:463–477. doi: 10.1016/j.pneurobio.2010.08.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci. 2014;8:388. doi: 10.3389/fncel.2014.00388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11:720–731. doi: 10.1016/S1474-4422(12)70104-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Fu Y, Hao J, Zhang N, Ren L, Sun N, Li YJ, et al. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proofof- concept study. JAMA Neurol. 2014;71:1092–1101. doi: 10.1001/jamaneurol.2014.1065. [DOI] [PubMed] [Google Scholar]
  • [9].Kim JY, Kawabori M, Yenari MA. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets. Curr Med Chem. 2014;21:2076–2097. doi: 10.2174/0929867321666131228205146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Zhou Y, Wang Y, Wang J A, Stetler R, Yang QW. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol. 2014;115:25–44. doi: 10.1016/j.pneurobio.2013.11.003. [DOI] [PubMed] [Google Scholar]
  • [11].Fang H, Wang PF, Zhou Y, Wang YC, Yang QW. Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury. J Neuroinflammation. 2013;10:27. doi: 10.1186/1742-2094-10-27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Moxon-Emre I, Schlichter LC. Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. J Neuropathol Exp Neurol. 2011;70:218–235. doi: 10.1097/NEN.0b013e31820d94a5. [DOI] [PubMed] [Google Scholar]
  • [13].Aronowski J, Hall CE. New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res. 2005;27:268–279. doi: 10.1179/016164105X25225. [DOI] [PubMed] [Google Scholar]
  • [14].Gao Z, Wang J, Thiex R, Rogove AD, Heppner FL, Tsirka SE. Microglial activation and intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:51–53. doi: 10.1007/978-3-211-09469-3_11. [DOI] [PubMed] [Google Scholar]
  • [15].Hickenbottom SL, Grotta JC, Strong R, Denner LA, Aronowski J. Nuclear factor-kappaB and cell death after experimental intracerebral hemorrhage in rats. Stroke. 1999;30:2472–2477. doi: 10.1161/01.STR.30.11.2472. [DOI] [PubMed] [Google Scholar]
  • [16].Wang J, Dore S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007;27:894–908. doi: 10.1038/sj.jcbfm.9600357. [DOI] [PubMed] [Google Scholar]
  • [17].Guo FQ, Li XJ, Chen LY, Yang H, Dai HY, Wei YS, et al. Study of relationship between inflammatory response and apoptosis in perihematoma region in patients with intracerebral hemorrhage. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2006;18:290–293. [PubMed] [Google Scholar]
  • [18].Liesz A, Ruger H, Purrucker J, Zorn M, Dalpke A, Mohlenbruch M, et al. Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases. PLoS One. 2013;8:74839. doi: 10.1371/journal.pone.0074839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Shah IM, Macrae IM, Di Napoli M. Neuroinflammation and neuroprotective strategies in acute ischaemic stroke - from bench to bedside. Curr Mol Med. 2009;9:336–354. doi: 10.2174/156652409787847236. [DOI] [PubMed] [Google Scholar]
  • [20].Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol. 2007;184:53–68. doi: 10.1016/j.jneuroim.2006.11.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O, Hartman R, et al. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp Neurol. 2013;241:45–55. doi: 10.1016/j.expneurol.2012.12.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Albelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J. 1994;8:504–512. [PubMed] [Google Scholar]
  • [23].Dziedzic T, Bartus S, Klimkowicz A, Motyl M, Slowik A, Szczudlik A. Intracerebral hemorrhage triggers interleukin-6 and interleukin-10 release in blood. Stroke. 2002;33:2334–2335. doi: 10.1161/01.STR.0000027211.73567.FA. [DOI] [PubMed] [Google Scholar]
  • [24].Weng JC, Wu SK, Lin WL, Tseng WY. Detecting bloodbrain barrier disruption within minimal hemorrhage following transcranial focused ultrasound: a correlation study with contrast-enhanced MRI. Magn Reson Med. 2011;65:802–811. doi: 10.1002/mrm.22643. [DOI] [PubMed] [Google Scholar]
  • [25].Barr TL, Latour LL, Lee KY, Schaewe TJ, Luby M, Chang GS, et al. Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke. 2010;41:123–128. doi: 10.1161/STROKEAHA.109.570515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Davalos A, et al. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke. 2005;36:86–91. doi: 10.1161/01.STR.0000149615.51204.0b. [DOI] [PubMed] [Google Scholar]
  • [27].Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M. Collagenase-induced intracerebral hemorrhage in rats. Stroke. 1990;21:801–807. doi: 10.1161/01.STR.21.5.801. [DOI] [PubMed] [Google Scholar]
  • [28].Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland B d, Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab. 1999;19:624–633. doi: 10.1097/00004647-199906000-00005. [DOI] [PubMed] [Google Scholar]
  • [29].Abilleira S, Montaner J, Molina CA, Monasterio J, Castillo J, Alvarez-Sabin J. Matrix metalloproteinase-9 concentration after spontaneous intracerebral hemorrhage. J Neurosurg. 2003;99:65–70. doi: 10.3171/jns.2003.99.1.0065. [DOI] [PubMed] [Google Scholar]
  • [30].Yong VW. Metalloprote inases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci. 2005;6:931–944. doi: 10.1038/nrn1807. [DOI] [PubMed] [Google Scholar]
  • [31].Sun C, Wang Q, Zhou H, Yu S, Simard AR, Kang C, et al. Antisense MMP-9 RNA inhibits malignant glioma cell growth in vitro and in vivo. Neurosci Bull. 2013;29:83–93. doi: 10.1007/s12264-012-1296-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

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